What causes long COVID? The answer might be in your gut

Nearly one in five people who have had COVID-19 in the United States continue to suffer from symptoms of long COVID. But why some people recover completely while others remain sick has been a mystery. Now research has provided some enticing clues.

A new study shows that bits of virus that survive in the gut cause chronic inflammation, which reduces production of serotonin—a molecule critical for communication between nerve cells in the gut and brain. The authors of the new article suggest that depletion of serotonin disrupts gut-to-brain communication, which can cause long-term neurological symptoms such as “brain fog” and impaired memory.

This may explain how “long COVID might be linked through a pathway that originates in the gut and leads to serotonin reduction,” says Christoph Thaiss, a microbiologist at the University of Pennsylvania, who led the study.

“These are very important findings that help explain why serotonin levels remain low in certain long COVID patients following SARS-CoV-2 infection,” says Liam O’Mahony, an immunologist at APC Microbiome Ireland, University College Cork, who was not involved in Thaiss’ work.

Links between the gut and brain

The brain and the gut talk to each other. In fact, the gastrointestinal nervous system with its own 500 million neurons is so large, it is sometimes called the “second brain.”

“That’s why when you’re feeling stressed, you can get abdominal pain or diarrhea,” says Kenji Hashimoto, a neuroscientist at Chiba University in Japan.

The longest of the brain nerves, called vagus nerve connects with gut and uses the neurotransmitter serotonin to communicate and regulate many biological and neurological functions such as mood, digestion, appetite, learning and memory, immune response, and heart rate, among others, says Éric Boilard, an immunologist at Laval University in Quebec City, Canada.

About 95 percent of the serotonin is produced in the gut, although the brain makes its own supply. Microbes that live in our gut also produce chemical neurotransmitters, including serotonin. While serotonin produced in the gut does not directly reach the brain, it can influence the brain via neuronal circuits through vagus nerve.

“We’ve known that the gut is a reservoir for virus for a long time,” says Melanie Gareau, a microbiologist at University of California, Davis. What is exciting is that “we’re starting to identify messengers from the gut that signal to the brain.”

Causes of neurological symptoms

Scientists have proposed several possible mechanisms that may cause long COVID. An abnormal immune response that triggers ongoing inflammation after the acute infection is one explanation, says David Sahner, a senior data adviser to National Center for Advancing Translational Sciences in Bethesda.

Previous studies had shown that fragments of SARS-CoV-2 virus that linger in patients after the initial infection heals can cause chronic inflammation, auto-antibody development, tissue damage, and in some cases disrupt communication in the nervous system.

COVID-19 also interferes with the levels of several metabolites during the initial infection. Patients not only have lower levels of serotonin but these imbalances can persist in those with long COVID.

Thaiss and his colleagues set out to find if and how all these factors are related?

They began by comparing the level of metabolites in blood samples of long COVID patients and healthy volunteers. They found that serotonin levels in blood were so different, they could predict whether a patient had fully recovered or had developed long COVID.

The long COVID patients also had changes in the blood levels of amino acids—the building blocks of proteins—compared to healthy patients. One, called tryptophan, stood out, because it was suppressed in long COVID patients. Humans need tryptophan from food to produce serotonin. That suggests that chronic inflammation caused by viral remnants lowers absorption of tryptophan from food, which then lowers blood serotonin.

Thaiss’ team also confirmed that some long COVID patients continue to excrete bits of SARS-CoV-2 virus in their stool even months after recovering from COVID-19. These remnants of the virus, called a viral reservoir, trigger the immune system to release virus fighting proteins called interferons. The extended release of interferons caused chronic inflammation in lab mice and in the long COVID patients.

Blocking interferon kept serotonin levels high in mice. The scientists confirmed that low absorption of tryptophan from food was the reason for low serotonin levels in virus-infected mice.

“The serotonin reduction affects the vagus nerve,” says Thaiss. Reduced serotonin levels due to viral infections in mice disrupted their vagus nerve signaling and mice failed to distinguish new objects from familiar ones in tests. This failure mimics neurological symptoms, such as brain fog, generally associated with long COVID in humans.

Some common antidepressant drugs, called selective serotonin reuptake inhibitors (SSRIs), such as Prozac and Sarafem boost mood by increasing serotonin in the brain. When scientists gave Prozac to sick mice, it improved their performance in recognition tests. Supplementing the mouse food with tryptophan, which improved levels of serotonin, also helped.

This new research identifies mechanisms that contribute to depleted blood levels of serotonin, says O’Mahony.

“I think we have a few actionable items about long COVID, that we can now look at in clinical trials,” says Thaiss.

Can boosting serotonin levels treat long COVID?

The new study suggests SSRI’s might be useful in treating, or even preventing long-COVID. When scientists gave Prozac to the lab mice—whose neurological symptoms mimicked long COVID because of viral infection—it restored their memory loss.

A study that has not yet been peer reviewed, shows that COVID patients already on SSRI had 25 percent less risk of developing long-COVID.

“Initiating use of SSRIs prior to diagnosis of COVID-19 may be effective in reducing the risk of long-COVID,” says Hythem Sidky, a computational biologist, who led the study for the National COVID Cohort Collaborative (N3C) at the National Institutes of Health.

But whether SSRIs can cure long COVID, “remains to be determined,” says Sahner, who co-led the N3C study with Sidky.

Further research is needed to establish which serotonin boosting drug and at what dosage may help in treatment of long COVID. Fluvoxamine, an SSRI known under the brand names Luvox and Faverin, which is prescribed to treat major depressive disorder, obsessive–compulsive disorder, and post-traumatic stress disorder did not prevent long COVID although it prevented severe COVID-19 at higher doses.

“Giving fluvoxamine at a dose of 50 milligrams twice a day during acute infection did not prevent the development of long-COVID,” says Carolyn Bramante, an internist at University of Minnesota, Minneapolis. Bramante led a trial that followed overweight or obese patients for 10 more months after treating their original COVID-19 infection with fluvoxamine. “It did prevent severe COVID at a higher dose,” says Bramante. “But high doses are complicated with this drug.”

In the meantime, scientists warn patients against self-medicating with antidepressants to treat long COVID. If the levels of serotonin in brain become too high, it can cause serotonin syndrome—a rare but serious condition with symptoms such as seizures, irregular heartbeat, and unconsciousness.

“We’re going to need several ways to both prevent long-COVID and treat it,” says Bramante. “But people should only act in connection with their physician and in ways that are supported by data.”

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